Humans are colonized from birth with trillions of bacteria, the majority of which reside within the intestinal tract and constitute the gut microbiota (Turnbaugh et al., Nature 449, 804-810 (2007)). Over the millennia the intestinal immune system has co-evolved with the gut microbiota to develop a number of highly regulated interactions required for the maintenance of intestinal health. Disruption of this homeostasis leads to intestinal inflammation and is generally regarded as a root cause of inflammatory bowel disease (Hooper, et al., Science 336, 1268-1273 (2012)).
Regulatory T cells (Treg) are a subpopulation of T cells that are capable of modulating immune responses, and in particular modulating autoimmune responses. Those Treg expressing the transcription factor Foxp3 (i.e., Foxp3+ Treg) are particularly important for limiting intestinal inflammation (Izcue, et al. Rev. 212, 256-271 (2006); Josefowicz, et al. Annu. Rev. Immunol. 30, 531-564 (2012)). Colonic regulatory T cells (cTreg) represent a subpopulation of Treg that are active in the gastrointestinal tract and are critical for regulating intestinal inflammation. Germ-free mice, which lack bacteria, have decreased numbers of cTreg and as a result are more susceptible to certain experimental colitis models, therefore suggesting that cTreg depend on signals derived from the microbiota for their proper development and function (Geuking et al., Immunity 34, 794-806 (2011); Atarashi et al., Science 331, 337-341 (2011); Maslowski et al., Nature 461, 1282-1286 (2009); Atarashi, et al., Semin. Immunol. 23, 146-153 (2011)).
To date, it remains unclear how gut microbiota induce cTreg responses, and the identification of compounds that promote adaptive immune maturation and influence intestinal Treg and cTreg remain critical to understanding how intestinal homeostasis is maintained and how it can be optimized to promote health. Additionally, novel therapies are needed for modulating autoimmune and inflammatory responses, and in particular autoimmune and immune responses affecting the gastrointestinal tract. Particularly needed are safe and effective therapies that are capable of inducing (e.g., enhancing) a subject's ability to mount an immune response. Also needed are safe and effective therapies that enhance the production and/or activation, or otherwise increase the quantity and/or function of, Treg in the gastrointestinal tract of a subject.